title: X-linked deafness-2 (DFNX2) phenotype associated with a paracentric inversion upstream of POU3F4.
abstract: OBJECTIVE
  The authors report on a 7-year-old male, designated FR, who has severe sensorineural hearing loss. Features include a round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns regarding FR, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. Genetic studies were performed to investigate genetic causes for his hearing loss.
  
  
  METHODS
  History, physical examination, audiologic assessment, and imaging were performed according to usual practice. FMR1,GJB2,GJB6, and POU3F4 genes were sequenced. Chromosomal studies consisted of karyotyping and breakpoint analysis by fluorescence in situ hybridization (FISH).
  
  
  RESULTS
  Results from FMR1,GJB2,GJB6, and POU3F4 sequencing and echocardiography, electrocardiogram, and abdominal ultrasound were normal. A computed tomography (CT) scan revealed a large fundus of the internal auditory canals and absence of the bony partition between the fundus and the adjacent cochlear turns, with a widened modiolus bilaterally. FR's CT findings were consistent with those described in persons with X-linked deafness-2 (DFNX2) hereditary deafness. FR's karyotype was 46,inv(X)(q13q24),Y.ish inv(X)(XIST+)mat. FISH refined the breakpoints to inv(X)(q21.1q22.3). The Xq21.1 breakpoint was narrowed to a 25-kb region 450 kb centromeric to the DFNX2 gene, POU3F4. There are rare case reports of DFNX2 patients with chromosomal rearrangements positioned centromeric to POU3F4 and no mutations within the gene.
  
  
  CONCLUSIONS
  Authors hypothesized that FR's hearing loss was caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anger
authors.forename: Susan
authors.initials: S
authors.lastname: Crocker
authors.forename: Kyle
authors.initials: K
authors.lastname: McKenzie
authors.forename: Kerry K
authors.initials: KK
authors.lastname: Brown
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: Karen
authors.initials: K
authors.lastname: Harrison
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: MacKenzie
mesh_terms: D002648:Child; D007446:Chromosome Inversion; D041321:Chromosomes, Human, X / Q000235:genetics*; D000072259:Connexin 26; D017630:Connexins; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000503:physiopathology; D005838:Genotype; D006314:Hearing Loss, Conductive / Q000235:genetics* / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D050809:POU Domain Factors / Q000235:genetics*; D010641:Phenotype
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D050809:POU Domain Factors; C091774:POU3F4 protein, human; D000072259:Connexin 26